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However, the interactions among these pathogens and their combined effects on disease severity are not well understood. The study investigates the interactions among co-infecting enteric pathogens on diarrhea pathogenesis within an epidemiological framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This large-scale, multicenter case-control study was conducted from January 1, 2024 to December 31, 2024, across four tertiary hospitals in Guangzhou, Guangdong Province, China. Stool samples were collected from children under five\u00a0years with diarrhea (cases) and those without (non-diarrheal children). 21 enteric pathogens in each specimen were identified. Potential interactions between co-infecting pathogens were assessed using both additive and multiplicative models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Enteric pathogens were more frequently detected in children with diarrhea than in non-diarrheal children (53.6% vs. 27.8%,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), with significantly higher detection of both viral (23.3% vs. 13.3%) and bacterial pathogens (34.2% vs. 12.5%). Pathogens independently associated with diarrhea included diarrheagenic\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      (DEC),\n                      <jats:italic>Vibrio parahaemolyticus<\/jats:italic>\n                      ,\n                      <jats:italic>Clostridioides difficile<\/jats:italic>\n                      (CD), group A rotavirus (RVA), and Norovirus GII (NoVs GII). The proportion of children with any form of co-infection was also significantly higher in the diarrhea group compared with\u00a0non-diarrheal children (16.1% vs. 4.5%,\n                      <jats:italic>\u03c7<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u200932.594,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001). Several specific dual-pathogen combinations\u2014namely RVA\u2009+\u2009DEC (\n                      <jats:italic>\u03c7<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20094.956,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.026), RVA\u2009+\u2009CD (\n                      <jats:italic>\u03c7<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u200910.313,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), RVA\u2009+\u2009NoVs GII (\n                      <jats:italic>\u03c7<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u200915.503,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), and DEC\u2009+\u2009\n                      <jats:italic>Blastocystis hominis<\/jats:italic>\n                      (Bh)\u2014were significantly more common among diarrhea cases (\n                      <jats:italic>\u03c7<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20094.207,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.041). Multiplicative interaction analysis further identified significant synergistic effects for RVA\u2009+\u2009DEC [odds ratio (\n                      <jats:italic>OR<\/jats:italic>\n                      )\u2009=\u20092.304, 95% confidence interval (\n                      <jats:italic>CI<\/jats:italic>\n                      ): 1.194\u20135.089], RVA\u2009+\u2009CD (\n                      <jats:italic>OR<\/jats:italic>\n                      \u2009=\u20096.199, 95%\n                      <jats:italic>CI:<\/jats:italic>\n                      1.701\u201310.601), RVA\u2009+\u2009NoVs GII (\n                      <jats:italic>OR<\/jats:italic>\n                      \u2009=\u20096.296, 95%\n                      <jats:italic>CI:<\/jats:italic>\n                      2.061\u201310.723), and DEC\u2009+\u2009Bh (\n                      <jats:italic>OR<\/jats:italic>\n                      \u2009=\u20094.602, 95%\n                      <jats:italic>CI:<\/jats:italic>\n                      2.213\u20139.878).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates the frequent occurrence of co-infections in\u00a0diarrheal\u00a0children, and enteric pathogens may interact synergistically or antagonistically. It highlights the central role of RVA in exacerbating the severity of these co-infections. The findings emphasize the critical role of RVA vaccination in alleviating the burden and severity of diarrhea.<\/jats:p>\n                    <jats:p>\n                      <jats:italic>Trial Registration<\/jats:italic>\n                      The study was registered in the Chinese Clinical Trial Registry (ChiCTR-ROC-17013620).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s40249-025-01392-8","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T01:43:33Z","timestamp":1764639813000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Co-infection and interaction of enteric pathogens in acute diarrhea among children under five years: a large-scale multicenter observational study from China"],"prefix":"10.1186","volume":"14","author":[{"given":"Shun-Xian","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin-Yan","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Xin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Chun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu-Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Guang","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Wen","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Tao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang-Hua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Fu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can-Jun","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Zhu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"issue":"5","key":"1392_CR1","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/S1473-3099(24)00691-1","volume":"25","author":"A Vongpradith","year":"2025","unstructured":"Vongpradith A, Dominguez RM, Ma J, Albertson SB, Novotney A, Khalil IA, et al. 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